Lactamimide derivatives

ABSTRACT

WHEREIN X REPRESENTS OXYGEN OR SULFUR; A REPRESENTS A BOND, OR A STRAIGHT OR BRANCHED SLKYLENE CHAIN OF FROM 1 TO 3 CARBON ATOMS; R REPRESENTS HYDROGEN, A STRAIGHT OR BRANCHED LOWER ALKYL GROUP OF 1 TO 4 CARBON ATOMS, A STRAIGHT OR BRANCHED LOWER ALKENYL GROUP OF FROM 3 TO 6 CARBON ATOMS, A CYCLOALKYL GROUP OF FROM 3 TO 6 CARBON ATOMS OR PHENYL; R1 REPRESENTS HYDROGEN OR A STRAIGHT OR BRANCHED LOWER ALKYL GROUP OF FROM 1 TO 4 CARBON ATOMS; N IS N INTEGER OF FROM 3 TO 11; AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS AND INDIVIDUAL OPTICAL ISOMERS OF THE COMPOUNDS WHERE APPLICABLE.   (-X-CH=CH-CH=)&gt;C-A-CH(-R)-N=C&lt;(-(CH2)N-NH-)(-R1)   NOVEL COMPOUNDS USEFUL AS HYPOGLYCEMIC AGENTS ARE REPRESENTED BY THE FORMULA

United States Patent Ofice 3,816,457 Patented June 11,, 1974 ABSTRACT OF THE DISCLOSURE Novel compounds useful as hypoglycemic agents are represented by the formula wherein X represents oxygen or sulfur; A represents a bond, or a straight or branched alkylene chain of from 1 to 3 carbon atoms; R represents hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, a cycloalkyl group of from 3 t 6 carbon atoms or phenyl; R represents hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; n is an integer of from 3 to 11; and pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds where applicable.

FIELD OF INVENTION This invention relates to novel lactamimide derivatives useful as hypoglycemic agents and to methods of using the compounds either alone or in the form of pharmaceutical preparations.

SUMMARY OF INVENTION Lactamimide derivatives of the following Formula I and pharmaceutically acceptable acid addition salts and individual optical isomers where applicable are useful as hypoglycemic agents.

In the above Formula I, X represents oxygen or sulfur; A represents a bond or a straight or branched alkylene chain of from 1 to 3 carbon atoms; R represents hydrogen, or a straight or branched lower alkyl group from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms or phenyl; R represents hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; and n is an integer of from 3 to 11. Pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds where applicable are also included within the scope of this invention.

DETAILED DESCRIPTION OF INVENTION For convenience and uniformity all the compounds of this invention are named and represented as Z-iminoperhydroazacarbocyclics, as represented by general Formula I. It is well known, however, that compounds of this Formula I type may also be represented by the tautomeric form illustrated by the following Formula II:

R Formula II This tautomerism has been discussed by R. Kowk and P. Pranc, J. Org. Chem. 32, 740 (1967). The compounds of this invention when represented by Formula II will be named differently than when represented by Formula I. In solution under the conditions of therapeutic utility the proportion of each tautomeric form, or the delocalization of the charge between the two nitrogens, will be dependent upon numerous factors including the nature of the substituents, the pH of the medium, and the like. This equilibrium state is conveniently depicted by the following Formula II-I.

R H N m J 5 or W A H-Nm 011, X KI.)

R1 Formula III In the above Formulas II and III, X, A, R, R and n have the meanings defined hereinbefore.

As examples of straight or branched lower alkyl groups of from 1 to 4 carbon atoms which R and R may represent in the above Formulas I to I11 there may be mentioned methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, and the like.

As examples of alkenyl groups of from 3 to 6 carbon bon atoms which R may represent in the above Formulas I to HI there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As examples of alkenyl groups of from 3 to 6 carbon atoms which R may represent in the above Formulas I to III there may be mentioned allyl, Z-butenyl, 3-butenyl, 3-pentenyl, and the like.

Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acids. Suitable inorganic acids are for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids, and the like. Suitable organic acids are, for example, carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, rnalonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, and the like, or sulfonic acids such as methane sulfonic, Z-hydroxyethane sulfonic acid and the like.

As examples of compounds of this invention there may be mentioned:

2-[ [oz- 2-thienyl benzyl] imino] azacyclotridecane,

hexahydro-Z- 2-thenylimino azepine,

hexahydro-2-[ l- 2-thenyl propylimino] azepine,

2- furfurylimino hexahydroazepine,

2-[ [a- (2-furyl benzyl] imino] octahydroazocine,

hexahydro-2-[ [a-(2-thienyl)benzyl]irnino1azepine,

2-[ l- (Z-thenyl propylimino] pyrrolidine,

2-[ (u-cyclopropyl-2-thenyl imino] hexahydroazepine,

hexahydro-2- [B- Z-thienyl isopropylimino] azepine,

hexahydro-2- 2- 3- [Z-thienyl] butyl imino] azepine,

hexahydro-Z- [2-( l- [Z-thienyl] pent-4-enyl) imino] azepine,

2- [2-( 1- [2-furyl] pent-4-enyl imino] azacyclododecane,

2- (oc- [2-thienyl1benzyl) imino] piperidine,

5-tert-butylhexahydro-2- l- (Z-thienyl) -2-butylimino azepine,

2- (a-cyclopropyl-2-thenyl) imino1piperidine,

octahydro-2- (oc- [Z-thienyl] benzyl) imino azocine,

octahydro-2-[ 1- Z-thienyl) -2-butylimino] azocine, 2-[ a-cyclopropyl-2-thenyl imino] octahydroazocine, 2- l- (Z-thienyl -2-butylimino piperidine, octahydro-Z- 1- (Z-thienyl -2-butylimino] azonine, 2- (a- [2-furyl] benzyl imino] hexahydroazepine, 2-[ (a- [2-furyl] benzyl) imino piperidine, hexahydro-2- 3- [4- (Z-furyl) -4-cyclopentyl] butylimino azepine, 2- (Z-thenylimino) azacycloundecane, S-n-propylhexahydro-Z- (2- 1- (2-furyl) hex-4-enyl] imino azepine,

and the like and pharmaceutically acceptable acid addition salts thereof.

The compounds of this invention are useful as hypoglycemic agents and may be used to control hyperglycemic conditions, such as occur for example in diabetic patients, by inducing a hypoglycemic response in the patient. To illustrate the utility of the compounds of this invention male rats of the Charles River C.D. strain each weighing from 120 to 140 grams were fastened for 15 hours then injected subcutaneously with 1 g./kg. of body weight of glucose in 0.5 ml. of 0.9% sodium chloride solution. Immediately following the glucose injection the animals were administered by oral intubation a compound of this invention in 0.5 ml. of carboxymethyl cellulose. Two hours after the test compound was administered blood was withdrawn from the animals and a quantitative analysis of glucose in the plasma was performed by use of the ultramicro glucose oxidase procedure as described by L. P. Cawley et al., Am. J. Clin. Path. 32, 195-200 (1959).

Animals administered carboxymethyl cellulose with no test compound served as a control. The results of this test are summarized in the following Table I.

These novel compounds can be administered to animals, warm blooded animals and particularly mammals, either alone or in the form of pharmaceutical preparations which contain the novel compounds suitable for oral or parenteral administration. Pharmaceutical preparations containing novel compounds of this invention and conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets and capsules, or liquid solutions, suspensions or elixirs for oral administration, or liquid solutions, suspensions, emulsions, and the like for parenteral administration. The quantity of compound administered can vary over a wide range to provide from about 0.1 mg./kg. (milligram per kilogram) to about 100 mg./kg. of body weight of the patient per day to achieve the desired efiect. Unit doses of these compounds can contain from about to 500 mg. of the compound and may be administered, for example, from 1 to 4 times daily. Specific Examples 25 to 28 are illustrative of pharmaceutical preparations containing as active ingredients compounds of this invention.

4 The compounds of this invention may be prepared by reacting an excess of a lactim ether of the formula N lower alkyl 0- 0 (CH R Formula IV with a primary amine of the following formula II X/ A CH NH: Formula V in a manner similar to that reported by R. E. Benson and T. L. Cairns in J. Am. Chem. Soc. 70, 2115-8 (1948). The various symbols X, A, R, R and n have the meanings defined hereinbefore. This reaction may be carried out with or without a solvent. When a solvent is employed that preferred is a lower alcohol, such as methanol, ethanol, isopropyl alcohol, butanol and the like. Other solvents, such as, aromatic hydrocarbons, for example, benzene and toluene may also be used as suitable solvents for this reaction. A basic or an acidic catalyst such as a tertiary amine or hydrogen chloride may be added to the reaction mixture. In general it is preferred that the hydrochloride salt of the amine be used in the reaction. The temperature of the reaction varies from 40 C. to C., and the preferred temperature is about 1525 C. The reaction time varies from 1 hour to about 60 days being dependent upon the temperature of the reaction, the reactant primary amine, and more particularly on the degree of steric hindrance of the amine since highly sterically hindered amines react very slowly.

The lactim others as represented by Formula IV which find use in this reaction may be prepared from commercially available corresponding lactams by methods known in the art. For example, by reaction of an appropriate lactam with dirnethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 2-24 hours the corresponding o-methyl lactim ether is obtained.

The amines as represented by Formula V which find use in this reaction may be prepared by several methods known to the art. For example, a nitrile of the formula H HA-CN X Formula VI may be reacted with an alkylor phenylmagnesium halide compound followed by reduction of the resulting ketimine complex in situ with lithium aluminum hydride. Also, nitriles of the formula RCN Formula VII via Hoffman or Curtius degradation, such as described by F. J. McCarty et al., J. Med. Chem. 11, 534 (1968), or as described by Van Zoeren in U.S. 2,367,702.

The compounds of this invention may also be prepared using a complex of an appropriate lactam of the formula Formula VIII R Formula IX wherein n and R have the meaning defined above, with phosphorus oxychloride, phosgene, borontrifluoride etherate, dimethylsulfate, hydrogenjhalide or a combination of two or more such reagents. Several attempts have been made to formulate the structure of these complexes, and one formulation includes the imino halide, that is, 2- chloro-4,5,6,7-tetrahydro-3g-azepine. However, none of the formulations have been unambiguously established. This reaction has been studied by H. Bredereck in a series of articles in Chem. Ber., 1953-1968, particularly in vol. 94, 2278 (1961) and vol. 97, 1403 (1964). The complex formed is reacted with an appropriate primary amine describedhereinabove in an aromatic hydrocarbon solvent such as benzene, toluene or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, dichloroethane, tetrachloroethylene or the like. The reaction temperature is limited by the boiling point of the solvent, however, in some cases it is advantageous to carry out the reaction at room temperature or with cooling 'at 0 to'40 C. depending on the reactants.

Similarly the above reaction may be carried out by using known thiolactim ethers such as S-methylthiocaprolactim [H. Behringer and H. Meier, Ann. 607, 73-91 (1957)], or by using thiolactams'wherein the latter case it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [1. Gautier and J. Renault, C. 'R. Acad. Sci. 234, (1952)].

Also by catalytic hydrogenation of an appropriate amino-pyridine derivative as described by T. Grave, I. Am. Chem. Soc. 46, 1460 (1924), M. Friefelder et al., J. Org. Chem. 29, 3730 (1964) and L. Birkhofer, Ber. 75, 429 (1942), compounds of this invention containing a pentamethyleneimine moiety may be obtained.

The following specific examples are illustrative of the invention.

EXAMPLE 1 2-[ [oc-(2-thieny1)benzyl]imino]azacyclotridecane hydrochloride To 6.4 g. (0.033 mole) of 2-azacyclotridecanone in 100 ml. of benzene is added 4.8 g. (0.031 mole) of phosphorus oxychloride. The mixture is stirred at room temperature for 4 hours after which 6.5 g. (0.029 mole) of 6 tallized and recrystallized from isopropyl alcohol-water to give 2-[ [u-(2-thienyl)benzyl]imino] azacyclotridecane hydrochloride, M.P. ISO-160 C. (dec.).

EXAMPLE 2 Hexahydro-Z-(Z-thenylimino) azepine hydrochloride A solution of 11.2 g. (0.0995 mole) of 2-thenylamine in 700 ml. of ether is acidified with ethereal hydrochloric acid after which the precipitate is collected and dried to give 2-thenylamine hydrochloride.

A mixture of 15.1 g. (0.101 mole) of the above obtained Z-thenylamine hydrochloride, ml. of o-methylcaprolactim and 5 ml. of ethanol is stirred with cooling under tap water until the exothermic reaction is complete. The mixture is allowed to stand at room temperature for about 4 hours with occasional stirring and the addition of sufiicient ethanol to prevent the mixture from solidifying. The mixture is then cooled to C. after which the precipitate is collected, recrystallized from acetonemethanol and dried to give hexahydro-2- (Z-thenylimino) azepine hydrochloride, M.P. 207-209 C. (dec.).

EXAMPLE 3 Hexahydro-2-[ 1- (Z-thenyl) propylamino] azepine hydrochloride A mixture of 12 g. (0.0625 mole) of 1-(2-thenyl)-lpropylamine hydrochloride and about 15 m1. of o-methylcaprolactim is allowed to stand at room temperature for 8 days with occasional stirring and the addition of sufiicient absolute ethanol to prevent solidification of the mixture. The mixture is cooled to -20 C., then the precipitate is collected, washed with ether, air dried and recrystallized from acetone-methanol to give hexahydro- 2 [1 thenylpropylimino]azepine hydrochloride, M.P. 187l87.5 C.

Following the general procedure of Example 3 only substituting for 1-[(2-theuyl)-1propylamine hydrochloride and o-methylcaprolactim respectively the amine hydrochloride and lactim ether listed in the following Table II the respective compounds as listed are obtained.

TABLE II Reaction Ex. time, No. Compound name, M.P., C. Amlue, H01 Lactrm, ether days 4.--.-- 2-[[ x-(2-fury1)benzyl]iminogoctahydroazocine hydrochloride, 255-256 (dec.) a-(2furyl)benzylamine o-Methylenantholactim 7 5 Hexahydro-2-fla-(2-thienyl benzylhminolazepine hydrochloride, 255-256 (dec.). a-(2-threnyl)benzylo-l\1ethyleaprolactim- 7 2.10.1118. 6.--..1. 2-[1-(Z-thenyl)propylimino1pyrrolidine hydrochloride, 109-111 (dec.) 1-(2 -t1 1ieny1)-2-butylo-Methylbutyrolactim... 29

. ermine. 7 2-[(a-cyclopropyl-2-thenyl)imino]hexahydroazepine hydrochloride, 207-209.... a-Cycl0pr0py12theny1- o-Methy1capr01actim.... 7

mine. 8...... Hexahydro-2-[,9-(2-thienylisopropy1imiuo]azepine hydrochloride, 177:5-180..-.. 6-(2-theinyl)isopropy1- -....-do a amine. 9 Hexahydro-2-[2-(3-[2-thieuyl1buty1)iminolazepine hydrochloride, 188-193 3-(2-thienyDbuty1- .--.do 6

amine. 10 Hexahydro-2-[2-(1-]2-thienyl]pent-4-enyl)imiuo]azepine hydrochloride, 143-146. 2-[1(2 -thieny1)pent-4- -.....do 7

eny amine. 11. 2-[(a-[Z-thienyl]benzyl)imino]piperidine hydrochloride, 198-200 u-(2-t hienyl)benzylo-Methy1valero1aetim 8 31111118. 12 5-tert-bu'tylhexahydro2-[1-(2-thienyl)-2-buty1imino]azepinehydrochloride,223- [1-(2- thieuyl)-2-butylo-Methyl-fi-(tert-butyl) 8 226. ammo. caprolactim. 13.. 2-[(aeycIoprOpylQ-thenyl)imino1piperidine hydrochloride, 172-174 a-Cyclopropyl-Z-thenylo-Methy1valerolactim-" 12 8.1111116. 14..-" Octahydro-2-{(a-[2-thienyl]benzyl)irnino]azocine hydrochloride, 280-281 a-(Z-thienyDbenzylo-methylenautholactim 8 amine. 15.- Octahydro-2-[1-(2-thierryl)-2-butylimino]azocine hydrochloride, 188-190 1-(2-thienyD-2-butyldo 10 amine. 16 2-[(a-cyclopropyl-2-thenyl)iminoloctahydroazocine hydrochloride, 202-204..-" a-gycol opropyl-2- -.....do 21 eny.arnrne. 17 2-[1-(2-th1eny1)-2-butyliminolpiperidine hydrochloride, 134-136 1-(2-t hieny1)-2-butyloMethylvalero1actim 13 more. 18..." Octahydro-2-[1-(2-thieny1)-2-butylimino]azonine hydrochloride, 173-175 .do o-Methylcapryllactim 12 19 2-[(a-[2-furyl]benzyl)iminoJhexahydroazepine hydrochloride 216-218 a-(2-furyl)benzylamine.- o-Methylcaprolactim-. 4 20 2-[a-[2-tury1]benzyl)imino]piperidine hydrochloride, 169171. 3

a-(Z-thienyDbenZylamine hydrochloride is added. Stirring is continued at room temperature for 1 hour then at reflux temperature for 4 hours. The resulting solution is allowed to cool to room temperature and stand over night after which it is washed with 2 N h ydrochloric acid. The organiclayer is separated and. washed with a saturated sodium chloride solution and dried over sodium sulfate.

a-(2-Iury1)benzylamine o-Methylvalerolactim.

EXAMPLE 21 I Z-(furfurylimino)hexahydroazepine hydrochloride A solution of 17.8 g. (0.183 mole) offurfurylamine in 700 ml. of ether is acidified with ethereal hydrochloric acid after which the precipitate is collected and dried to give furfurylamine hydrochloride, M.P. 138.5440 C.

A mixture of the above obtained furfurylamine hydro- The solvent is evaporated, and the resulting oil is cryschloride and 30 ml. of o-methylcaprolactim is allowed to stand at room temperature for 2 days with occasional stirring and the addition of sufficient ethanol to prevent the mixture from solidifying. The mixture is then cooled to 20 C. then the precipitate collected and recrystallized from methanol-acetone to give Z-(furfurylimino) hexahydroazepine hydrochloride, M.P. 149.5150.5 C.

EXAMPLE 22 2-(furfurylimino)azacycloundecane hydrochloride o-Methylvalerolactim To a refluxing solution of 100 g. (1.01 moles) of valerolactim in 350 ml. of dry benzene is added dropwise 125 g. (0.99 mole) of dimethyl sulfate. After refluxing overnight the mixture is treated with saturated potassium carbonate solution, dried and the solvent is evaporated. The product is distilled at 20 mm., B.P. 55-57 C.

EXAMPLE 24 Following the procedure of Example 22 only substituting for valerolactam, the appropriate molar equivalent amount of butyrolactam, caprolactam, enantholactarn, caprylolactam, and S-Iert-butylcaprolactam the following respective compounds are obtained.

o-methylbutyrolactim, B.P. 65-67 C. (100 mm.), o-methylcaprolactim, B.P. 60-65 C. (13.0 mm.), o-methylenantholactim, B.P. 4853 C. (2.0. mm), o-methylcaprylolactim, BP. 44-46 C. (0.5 mm.), o-methyl--tert-butylcaprolactim, B.P. 76-79 C. (0.4-

EXAMPLE 25 An illustrative composition for tablets is as follows:

Per tablet, mg. (a) Octahydro 2 [1 (2 thienyl) 2 butylimino]azonine hydrochloride 100 (b) Wheat starch (c) Lactose 33.5 (b) Sodium chloride, q.s.

A granulation obtained upon mixing lactose with the starch and granulated starch paste is dried, screened and mixed with the active ingredient (a) and magnesium stearate. The mixture is compressed in tablets weighing 150 mg. each.

EXAMPLE 26 An illustrative composition for hard gelatin capsules is as follows:

Per capsule, mg. (a) Hexahydro 2 [2 (1 [2 thienyl] pent- 4-enyl)imino]azepine hydrochloride 150 (b) Talc i The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 175 mg. per capsule.

EXAMPLE 27 An illustrative composition for pills is as follows:

Per pill, mg. (a) 2 [[a (2 furyl)benzyl]imino] octahydroazocine hydrochloride 150 (b) Corn starch 120 (c) Liquid glucose 15 The pills are prepared by blending the active ingredient and starch then adding the liquid glucose with thorough kneading to form a plastic mass. The pills are then out and formed from the plastic pill mass.

volume basis. (a) 2 [(oz cyclopropyl 2 thenyl)imino] hexahydroazepine hydrochloride mg (b) Sodium chloride, q.s. (0) Water for injection to make ..ml 10 The composition is prepared by dissolving the active ingredient and suflicient sodium chloride in water for injection to render the solution isotonic. The composition may be dispensed in a single ampule containing 100 mg. of the active ingredient for multiple dosage or in 10 ampules for a single dosage.

What is claimed is:

1. A compound selected from a base of the formula H R N K A-( 3H-N=C (CH1) wherein X is selected from oxygen or sulfur; A is selected from the group representing a bond or a straight or branched alkylene chain of from 1 to 3 carbon atoms; R is selected from the group consisting of hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, a cycloalkyl group of from 3 to 6 carbon atoms and phenyl; R is selected from the group consisting of hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; 11 is an integer of from 3 to 11; and pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein X is oxygen.

3. A compound of claim 2 which is 2-[(a-[2-furyl] benzyl)imino]hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.

4. A compound of claim 2 which is 2[[a-(2furyl)- benzyl1imino]octahydroazocine and pharmaceutically acceptable acid addition salts thereof.

5. A compound of claim 1 wherein X is sulfur.

6. A compound of claim 5 which is octahydro-Z-[l-(Z- thienyl) 2 butylimino]azonine and pharmaceutically acceptable acid addition salts thereof.

7. A compound of claim 5 which is hexahydro-2-[2-(1- [2-thienyl1pent 4 enyl)imino1azepine and pharmaceutically acceptable acid addition salts thereof.

8. A compound of claim 5 which is heXahydro-Z-Ha- (2- thienyl)benzyl]imino]azepine and pharmaceutically acceptable acid addition salts thereof.

9. A compound of claim 5 which is 2-[a-cyclopropyl- 2-thenyl)imino]hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.

References Cited UNITED STATES PATENTS 3,255,181 6/1966 Gatzi 260-239 3,634,401 1/ 1972 Gatzi 260-239 3,658,901 4/1972 Timmons et al. 260-551 3,483,231 12/1969 Marcus et al. 260-396 3,436,402 4/1969 Cassady et al. 260-3263 3,344,153 9/1967 Kiihle et al. 260-3472 3,223,733 12/1965 Heiss et a1 260-566 HENRY R. J ILES, Primary Examiner C. M. S. JAISLE, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 5, 57

DATED 1 June 11, 197 i V I J .Martin G risar, George P .Claxton, Thomas R.Blohm It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:v

Column 2, line 32, "As examples of alkenyl groups... should read "As examples of cycloalkyl group's". Column 6, line 2 l, "propylaminHazepine" should read "propylimino)azepine". Column 7, line +7, '(b) sodium chloride, q.s." should read "(d) magnesium stearate 1.5 mg".

This certificate supersede Certificate of Correction issued January 6, 1976.

Signed and Sealed this Third Day of August 1976 [SEAL] A ttesr:

RUTH c. MASON c. MARSHALL DANN :HH II'HX fj iv ('lmzmisximu-r uj'latenrs and Trademarks i read "As examples of cycloalkyl groups".

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,816, 57

DATED January 5, 973 |NV4ENTOR(5) I J Martin Gr i sar, George P. Claxton, Thomas R. Blohm It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: 4

Column 2, line 32, "As examples of alkenyl groups..." should Column 6, line E i, "propylaminolazepine" should read "propyliminolazepine". Column 7, l ine +7, (b) sodium chloride, q.s'." should read (d) magnesium stearate 1.5 mg".

Signed and Scaled this sixth D of January 1976 [SEAL] A ttest:

C. MARSHALL DANN Commissioner of Parents and Trademarks RUTH C. MASON Arresting Officer 

